U.S. patent number 6,231,528 [Application Number 09/232,101] was granted by the patent office on 2001-05-15 for ultrasonic and growth factor bone-therapy: apparatus and method.
Invention is credited to Alessandro Chiabrera, Jonathan J. Kaufman.
United States Patent |
6,231,528 |
Kaufman , et al. |
May 15, 2001 |
Ultrasonic and growth factor bone-therapy: apparatus and method
Abstract
Non-invasive therapeutic treatment of bone in vivo using
ultrasound in conjunction with application of a biochemical
compound or bone growth factor is performed by subjecting bone to
an ultrasound signal supplied to an ultrasound transducer placed on
the skin of a bony member, and involving a repetitive finite
duration signal consisting of plural frequencies that are in the
ultrasonic range to 20 MHz. Concurrent with application of the
ultrasound is the utilization of a bone growth factor applied to
the skin of a bony member before stimulation with ultrasound.
Ultrasonic stimulation is operative to transport the bone growth
factor to the bone and then to synergistically enhance the
interaction of the bone growth factor with the bone, whereby to
induce healing, growth and ingrowth responses. In another
embodiment, a vibrational or mechanical input together with a
biochemical compound enhances both bone fracture healing and treats
osteoporosis.
Inventors: |
Kaufman; Jonathan J. (Brooklyn,
NY), Chiabrera; Alessandro (16145 Genoa, IT) |
Family
ID: |
22871878 |
Appl.
No.: |
09/232,101 |
Filed: |
January 15, 1999 |
Current U.S.
Class: |
601/2; 600/439;
607/51 |
Current CPC
Class: |
A61N
7/00 (20130101); A61B 2017/564 (20130101) |
Current International
Class: |
A61N
7/00 (20060101); A61B 17/56 (20060101); A61B
017/56 () |
Field of
Search: |
;601/2
;604/19-22,890.1,892.1,289,290 ;607/50,51 ;600/439
;514/946,947,964,965 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Michael Hadjiargyrou et al., "Enhancement of Fracture Healing by
Low Intensity Ultrasound", Clinical Orthopaedics and Related
Research, 1998, No. 355S, pp. S216-S229. .
Thomas K. Kristiansen et al., "Accelerated Healing of Distal Radial
Fractures with the Use of Specific, Low-Intensity Ultrasound", The
Journal of Bone and Joint Surgery, 1997, vol. 79-A, No. 7, pp.
961-973. .
James D. Heckman et al., "Accelaration of Tibial Fracture-Healing
by Non-Invasive, Low-Intensity Pulsed Ultrasound", The Journal of
Bone and Joint Surgery, 1994, vol. 76-A, No. 1, pp. 26-34. .
W. J. W. Sharrard, "A Double-Blind Trial of Pulsed Electromagnetic
Fields for Delayed Union of Tibial Fractures", The Journal of Bone
and Joint Surgery, 1990 vol. 72-B, No. 3, pp. 347-355. .
John M. Wozney et al., "Bone Morphogenetic Protein and Bone
Morphogenetic Protein Gene Family in Bone Formation and Repair",
Clinical Orthopaedics and Related Research, 1998, No. 346, pp.
26-37. .
Kati Elima, "Osteoinductive Proteins", Annals of Medicine 25, 1993,
pp. 395-402. .
Mark E. Bolander, "Regulation of Fracture Repair by Growth
Factors", P.S.E.B.M. Growth Factors in Fracture Repair, 1992, vol.
200, pp. 165-170. .
Michael E. Joyce et al., "Transforming Growth Factor-B in the
Regulation of Fracture Repair", The Orthopedic Clinics of North
Amrica, Pathologic Fractures in Metabolic Bone Disease, 1990, vol.
21, No. 1, pp. 199-209. .
Stephen B. Trippel, "Growth Factors as Therapeutic Agents",
American Academy of Orthopaedic Surgeons, Rosemont, IL,
Instructional Course Lectures, vol. 46, 1997, Sec. VIII, Chapter
44, pp. 473-476. .
Stephen B. Trippel et al., "Growth Factor Treatment of Disorders of
Skeletal Growth", American Academy of Orthopaedic Surgeons,
Rosemont, IL, Instructional Course Lectures, vol. 46, 1997, Sec.
VIII, Chapter 45, 477-482. .
Thomas A. Einhorn et al., "Growth Factor Treatment of Fractures",
American Academy of Orthopaedic Surgeons, Rosemont, IL,
Instructional Course Lectures, vol. 46, 1997, Sec. VIII, Chapter
46, pp. 483-486. .
Richard D. Coutts et al., "Effect of Growth Factors on Cartilage
Repair", American Academy of Orthopaedic Surgeons, Rosemont, IL,
Instructional Course Lectures, vol. 46, 1997, Sec. VIII, Chapter
47, pp. 487-494. .
Gregory R. Mundi, "Growth Factors as Potential Therapeutic Agents
in Osteoporosis", American Academy of Orthopaedic Surgeons,
Rosemont, IL, Instructional Course Lectures, vol. 46, 1997, Sec.
VIII, Chapter 48, pp. 495-498. .
Stephen B. Trippel, "Growth Factor Actions on Articular Cartilage",
The Journal of Rheumatology, 1995, vol. 22:1, Suppl. 43, pp.
129-132. .
Samir Mitragotri et al., "Ultrasound-Mediated Transdermal Protein
Delivery", Science, vol. 269, Aug. 11, 1995, pp. 850-853. .
Samir Mitragotri et al, "A Mechanistic Study of
Ultrasonically-Enhanced Transdermal Drug Delivery", Journal of
Pharmaceutical Sciences, Jun. 1995, vol. 84, No. 6, pp.
697-706..
|
Primary Examiner: Lateef; Marvin M.
Assistant Examiner: Shaw; Shawna J
Attorney, Agent or Firm: Rader, Fishman & Grauer
PLLC
Claims
What is claimed is:
1. A method of non-invasively therapeutically treating bone tissue
in a living body, using an ultrasound transducer and an ultrasound
pulser, the method comprising the steps of:
(a) placing a prescribed amount of a bone growth factor on skin
overlying said bone tissue in said living body;
(b) acoustically coupling said ultrasound transducer to said skin
overlying said bone tissue of said living body;
(c) connecting said ultrasound transducer to said ultrasound pulser
and thereby generating an ultrasound signal within said skin and
said bone tissue;
(d) transporting said bone growth factor through said skin to said
bone tissue using said ultrasound signal, wherein said bone tissue
receives said bone growth factor applied exogenously; and
(e) exposing said bone tissue to said ultrasound signal in
conjunction with said bone growth factor
to produce a nonlinear interaction between said bone tissue, said
ultrasound signal and said exogenously applied bone growth
factor,
and to thereby synergistically promote bone tissue healing, growth
and repair.
2. The method according to claim 1, wherein said nonlinear
interaction includes diffusion of said bone growth factor molecules
by said ultrasound signal.
3. The method according to claim 1, wherein said nonlinear
interaction includes microstirring of said bone growth factor
molecules by said ultrasound signal.
4. The method according to claim 1, wherein said nonlinear
interaction includes binding of said bone growth factor molecules
to cells in said bone tissue.
5. The method according to claim 1, wherein said nonlinear
interaction includes a change in a binding constant associated with
said bone growth factor and cells in said bone tissue.
6. A method of therapeutically treating bone tissue in a living
body, using an ultrasound transducer and an ultrasound pulser, the
method comprising the steps of:
(a) injecting through skin overlying said bone tissue in said
living body a prescribed amount of a bone growth factor, wherein
said bone tissue receives said bone growth factor applied
exogenously;
(b) acoustically coupling said ultrasound transducer to said skin
overlying said bone tissue of said living body;
(c) connecting said ultrasound transducer to said ultrasound pulser
and thereby generating an ultrasound signal within said bone
tissue;
(d) exposing said bone tissue to said ultrasound signal in
conjunction with said bone growth factor, and
(e) continuing said exposing of step (d) for a time period to
produce a nonlinear interaction between said bone tissue, said
ultrasound signal and said exogenously applied bone growth
factor,
and to thereby synergistically promote bone tissue healing, growth
and repair.
7. The method according to claim 6, wherein said nonlinear
interaction includes diffusion of said bone growth factor molecules
by said ultrasound signal.
8. The method according to claim 6, wherein said nonlinear
interaction includes microstirring of said bone growth factor
molecules by said ultrasound signal.
9. The method according to claim 6, wherein said nonlinear
interaction includes binding of said bone growth factor molecules
to cells in said bone tissue.
10. The method according to claim 6, wherein said nonlinear
interaction includes a change in a binding constant associated with
said bone growth factor and cells in said bone tissue.
11. A method of therapeutically treating bone tissue in a living
body, the method comprising the steps of:
(a) injecting through skin overlying said bone tissue a prescribed
amount of a bone growth factor to said living body, wherein said
bone tissue receives said bone growth factor applied
exogenously;
(b) applying an electromagnetic stimulus to said bone tissue in
said living body, in conjunctive use with said application of said
bone growth factor; and
(c) continuing said applying of said electromagnetic stimulus for a
time period to cause displacements of said bone growth factor
received by said bone tissue to be nonlinearly modified, said
nonlinear modification arising from a concurrent use of said
electromagnetic stimulus and said bone growth factor,
and to synergistically promote bone tissue healing, growth and
repair.
12. The method according to claim 11, wherein said nonlinear
interaction includes diffusion of said bone growth factor molecules
by said electromagnetic stimulus.
13. A method of therapeutically treating bone tissue in a living
body, the method comprising the steps of:
(a) applying exogenously a prescribed amount of a bone growth
factor to said living body;
(b) applying a mechanical stimulus at sub-ultrasonic frequencies to
said bone tissue in said living body; and
(c) exposing said bone tissue to said mechanical stimulus in
conjunction with said bone growth factor for a prescribed period of
time
to produce a nonlinear interaction between said bone tissue, said
mechanical stimulus and said exogenously applied bone growth
factor,
and to thereby synergistically promote bone tissue healing, growth
and repair.
14. The method according to claim 13, wherein said nonlinear
interaction includes diffusion of said bone growth factor molecules
by said mechanical stimulus.
15. The method according to claim 13, wherein said nonlinear
interaction includes microstirring of said bone growth factor
molecules by said mechanical stimulus.
16. The method according to claim 13, wherein said nonlinear
interaction includes binding of said bone growth factor molecules
to cells in said bone tissue.
17. The method according to claim 13, wherein said nonlinear
interaction includes a change in a binding constant associated with
said bone growth factor and cells in said bone tissue.
18. A method of non-invasively therapeutically treating cartilage
tissue in a living body, using an ultrasound transducer and an
ultrasound pulser, the method comprising the steps of:
(a) placing a prescribed amount of a sodium hyaluronate compound on
skin overlying said cartilage tissue in said living body;
(b) acoustically coupling said ultrasound transducer to said skin
overlying said cartilage tissue of said living body;
(c) connecting said ultrasound transducer to said ultrasound pulser
and thereby generating an ultrasound signal within said skin and
said cartilage tissue, said connecting being kept during a
prescribed time period;
(d) transporting said sodium hyaluronate compound through said skin
to said cartilage tissue using said ultrasound signal, wherein said
cartilage tissue receives said sodium hyaluronate compound applied
exogenously; and
(e) exposing said cartilage tissue to said ultrasound signal in
conjunction with said sodium hyaluronate compound during said
prescribed time period,
to produce nonlinear interaction between said cartilage tissue,
said ultrasound signal and said sodium hyaluronate compound, said
nonlinear interaction arising from a concurrent use of said
ultrasound signal and said sodium hyaluronate compound during said
prescribed time period, and to synergistically promote cartilage
tissue healing, growth and repair.
19. A method of therapeutically treating cartilage tissue in a
living body, using an ultrasound transducer and an ultrasound
pulser, the method comprising the steps of:
(a) injecting through skin overlying said cartilage tissue in said
living body a prescribed amount of a sodium hyaluronate compound,
wherein said cartilage tissue receives said sodium hyaluronate
compound applied exogenously;
(b) acoustically coupling said ultrasound transducer to said skin
overlying said cartilage tissue of said living body;
(c) connecting said ultrasound transducer to said ultrasound pulser
and thereby generating an ultrasound signal within said cartilage
tissue; and
(d) exposing said cartilage tissue to said ultrasound signal in
conjunction with said sodium hyaluronate compound
to produce a nonlinear interaction between said cartilage tissue,
said ultrasound signal and said exogenously applied sodium
hyaluronate compound, said nonlinear interaction arising from a
concurrent use of said ultrasound signal and said sodium
hyaluronate compound during a prescribed time period,
and a to synergistically promote cartilage tissue healing, growth
and repair.
Description
FIELD OF THE INVENTION
The invention pertains generally to apparatus and method for
therapeutically treating musculoskeletal tissue in vivo. In
particular, the invention pertains to the combined use of
biophysical and biochemical stimuli for therapeutically treating
bone and other musculoskeletal tissue in vivo. More particularly,
the invention pertains to the combined use of ultrasound and a bone
growth factor for therapeutically treating bone in vivo.
BACKGROUND OF THE INVENTION
In recent years, various attempts have been made to stimulate bone
growth. These approaches have not been particularly successful, and
as a consequence have not as yet received broad acceptance by
either the professional (i.e., medical) or lay (i.e., patient)
community. Further, this lack of effectiveness has resulted in a
reluctance of the third-party payer community (e.g., insurance
companies and HMO's) to offer reimbursement, so that
commercialization of such stimulation technologies has been
stalled.
A number of issued patents disclose methods and apparatuses to
biophysically treat bone and other musculoskeletal tissue. For
example, Kaufman et al., U.S. Pat. No. 5,309,808 disclose apparatus
and method for therapeutically treating and/or quantitatively
evaluating bone tissue in vivo, by subjecting bone to an ultrasonic
signal pulse of finite duration, and involving a composite
sine-wave signal consisting of plural discrete frequencies. These
frequencies are spaced in the ultrasonic region to approximately 2
MHz; the excitation signal is repeated substantially in the range 1
to 1000 Hz. In a closely related patent, Kaufman et al., U.S. Pat.
No. 5,458,130, the same inventors extend the apparatus and method
to the treatment to musculoskeletal tissue in general. In another
patent by the same inventors, Kaufman et al., U.S. Pat. No.
5,547,459 disclose apparatus and method for therapeutically
treating bone tissue in vivo, by subjecting bone to an-ultrasonic
sinusoidal signal pulse peculiarly modulated by a sinusoidal signal
with a frequency between about 0 Hz and 25 kHz.
Duarte, U.S. Pat. No. 4,530,360 discloses apparatus and a method of
using ultrasonic energy for therapeutic treatment of bone tissue in
vivo, using a pulsed sine wave at substantially a single frequency
within the range 1.3 to 2.0 MHz, and at a pulse repetition rate of
100 to 1000 Hz.
McLeod et al., U.S. Pat. Nos. 5,103,806 and 5,191,880 disclose
methods for promotion of growth bone tissue and the prevention of
osteopenia, using mechanical loading of the bone tissue. In both
patents, the inventors apply a mechanical load to the bone tissue
at a relatively low level on the order of between about 50 and
about 500 microstrain, peak to peak, and at a relatively high
frequency in the range of about 10 and 50 hertz.
Bassett et al., U.S. Pat. No. 4,928,959 disclose method and device
for providing active exercise treatment for a patient suffering
from a bone disorder. A patient is subjected to an impact load in
order to stimulate bone growth, with an impact load sensor being
used to monitor the treatment strength.
Numerous other patents disclose methods for stimulating bone growth
relying on the generation of electromagnetic signals. For example,
Ryaby et al. U.S. Pat. Nos. 4,105,017 and 4,315,503 describe
methods for promoting bone healing in delayed and nonunion bone
fractures, using an asymmetric pulsed waveform. In U.S. Pat. No.
4,993,413, McLeod et al. disclose method and apparatus for inducing
a current and voltage in living tissue to prevent osteoporosis and
to enhance new bone formation. They disclose the use of a
symmetrical low frequency and low intensity electromagnetic signal
substantially in the range of 1-1000, hertz. In Liboff et al., U.S.
Pat. No. 5,318,551 (and others), methods are disclosed which
incorporate the combined use of a static and time-varying magnetic
field to stimulate bone healing and growth. Specific amplitudes and
frequencies are disclosed for optimal enhancement of bone growth,
based on the theory of "ion-cyclotron resonance."
Non-biophysical methods, i.e., methods which use a biochemical
compound (or generically a "bone growth factor") to stimulate bone
growth have also been described. For example, Ammann et al., U.S.
Pat. No. 5,604,204 disclose method for inducing bone growth using a
bone growth factor composition known as TGF-.beta., in an animal,
locally at a bone site where skeletal tissue is deficient. The
TGF-.beta. is contained in a "pharmaceutically acceptable carrier"
in an amount effective to induce bone growth at the bone site.
Dunstan et al., U.S. Pat. No. 5,656,598 disclose method involving
therapeutic (biochemical) compositions for the prevention and
treatment of pathological conditions involving bone and dental
tissue. The invention achieves its objectives by administering a
fibroblast growth factor (FGF-1) to an animal or human in need of
such treatment.
Oppermann et al., U.S. Pat. No. 5,354,557 and U.S. Pat. No.
5,814,604, disclose methods involving osteogenic devices. (The use
of the term "devices" should be understood to denote a biochemical
compound or bone growth factor in an appropriate matrix for
delivery to the bone.) The osteogenic devices are comprised of a
matrix containing substantially pure naturally-sourced mammalian
osteogenic protein. The Patents also disclose DNA and amino acid
sequences for novel polypeptide chains useful as subunits of
dimeric osteogenic proteins, and methods of using the osteogenic
devices to mimic the natural course of endochondral bone formation
in mammals. The inventors also disclose methods of producing
osteogenic proteins using recombinant DNA technology.
Balazs et al., U.S. Pat. No. 5,128,326, disclose systems based on
hyaluronans derivatives, as well as methods for preparing same.
Such systems are useful for treatment of cartilage tissue.
Falk et al., U.S. Pat. No. 5,792,753 disclose a pharmaceutical
composition which contains a drug that inhibits prostaglandin
synthesis, and also contains an amount of a form of hyaluronic
acid. The composition is topically administered to the skin and is
useful for the treatment of cartilage as it relates to
arthritis.
Wang et al., U.S. Pat. No. 4,877,864, disclose human and bovine
bone and cartilage inductive (biochemical) factors. Such factors
may be produced by recombinant techniques and may be useful for
treatment of various musculoskeletal tissue defects.
The prior art, exemplified by the references that have been briefly
discussed, have used either biophysical or biochemical approaches,
to promote bone growth, bone ingrowth and bone healing, or other
musculoskeletal tissue healing or growth. In either case, that is,
in the biophysical approach (including for example, ultrasound
methods), or in the biochemical approach (including, for example,
bone growth factors such as TFG-.beta.), treatment has not been
effective enough to lead to widespread use. However, the present
inventors have discovered how to dramatically enhance the efficacy
of such therapeutic methods for bone growth and other
musculoskeletal tissue healing, taking advantage of the uniquely
synergistic nature associated with the two basic approaches.
BRIEF STATEMENT OF THE INVENTION
It is accordingly an object of the invention to provide an improved
method and apparatus for therapeutically treating bone and other
musculoskeletal tissue in vivo, whereby to promote bone and other
musculoskeletal tissue healing, growth and ingrowth.
Another object is to meet the above object, such that bone and
musculoskeletal tissue healing, growth and ingrowth may be more
efficiently and more effectively treated than heretofore.
A specific object is to take advantage of the synergistic
properties associated with combined application of biochemical and
biophysical treatment methods whereby to achieve the indicated
objectives.
A further specific object is to take advantage of the synergistic
properties associated with biochemical and biophysical treatment
methods whereby to achieve much shorter total treatment times,
shortening both daily treatment times and the total number of daily
treatments required.
A further specific object is to achieve the above objects with a
specially chosen set of ultrasonic signals, designed with respect
to a mathematical model for evaluating the displacement associated
with a biochemical compound.
It is a general object to achieve the foregoing objects with
apparatus components that are for the most part commercially
available.
Briefly stated, the invention in its presently preferred form
achieves the foregoing objectives by injecting through skin
overlying a bone to be treated, a biochemical compound containing
an osteogenic protein (i.e., a bone growth factor). Soon after this
injection, the bone is iteratively subjected to an ultrasonic
signal of finite duration, consisting of frequency components in
the ultrasonic region to approximately 10 MHz, delivered by a
transducer placed on skin overlying the bone; the excitation signal
is repeated in the range of 1 to 1000 Hz. The exposure time for
ultrasonic therapy is chosen to be in the range of 1 minute to 1
hours for 1 to 3 times a day, for a period of days as necessary for
healing or for promoting bone growth or bone ingrowth. In the
presently preferred embodiment of the invention, a single
ultrasound treatment lasting for 15 minutes is applied within one
hour of the injection of the bone growth factor, and achieves the
indicated objectives.
In the currently preferred embodiment, the ultrasonic signal is
generated by a pulser to which the transducer is connected. The
pulser emits a negative going narrow square pulse of about -300
volts; the duration of the pulse itself is about 0.3 microseconds.
The transducer emits an ultrasound signal with a center frequency
of about 3 MHz, and of about 1 microsecond in duration, thereby
creating a broadband exponentially damped 3 MHz sinusoidal signal.
The signal is repeated at a repetition rate of 4,500 Hz.
In the presently preferred embodiment, the ultrasound interacts
with the bone growth factor in such a way as to enhance in a
positive fashion the bone healing, bone growth and bone ingrowth
processes. This combined effect of the ultrasound therapy in the
presence of the bone growth factor produces a synergistically
enhanced response, namely one that is many times more effective
than that which would be produced by having either agent acting
alone. In this way, the present invention, besides offering much
enhanced bone healing, bone growth and bone ingrowth results, also
benefits from significantly shorter treatment periods, both from
reductions in the total daily treatment time, but even more
importantly, from dramatic reductions in the total number of days
required for treatment, which result from application of the
methods disclosed herein.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an electrical-circuit diagram schematically showing the
interconnected relation of components of apparatus of the
invention.
FIGS. 2A and 2B are a set of acoustic ultrasonic signals used for
stimulation of bone growth and healing for several of the currently
preferred embodiments.
FIG. 3 is an electrical-circuit diagram schematically showing the
interconnected relation of components of apparatus of an
alternative embodiment of the invention.
FIG. 4 is a schematic diagram illustrating the interrelationships
of several alternative embodiments of the invention.
FIG. 5 is another schematic diagram illustrating the
interrelationships of several other alternative embodiments of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
The invention will be described in detail for a presently preferred
embodiment, in conjunction with the accompanying drawings. The
invention is shown in FIG. 1 in application to interconnected
components for constructing apparatus for performing methods of the
invention, namely for therapeutically treating bone in vivo,
whereby to stimulate bone growth, bone ingrowth and bone healing.
These components are, in general, commercially available from
different sources and will be identified before providing detailed
description of their total operation.
In FIG. 1, the bone locale 10 to be treated is shown surrounded by
soft tissue 11 and skin 9 and to be placed next to an ultrasonic
transducer 12, and obtainable from Panametrics, Inc., Waltham,
Mass.; suitably, the transducer 12 may be Panametrics "Videoscan"
part number V318-SU, having a nominal element size of 3/4"
diameter, and rated for 1 MHz. As shown, transducer 12 is used for
signal launching, in which the launched signal is transmitted
through standard ultrasonic couplant (not shown), through the skin,
soft tissue and into the bone tissue. The ultrasound couplant may
suitably be obtained from Parker Laboratories, Incorporated, of
Orange, N.J. In this way the ultrasound transducer may be
understood to be acoustically coupled to the skin 9.
Basic operation is governed by computer means 14, which may be a PC
computer, such as the "400 MHz Pentium II" available from Gateway
2000, Inc., North Sioux City, S. Dak.; as its designation suggests,
this computer contains a 400 MHz clock-pulse generator, and an
Intel Pentium II processor, with provision for keyboard instruction
at 14'.
An electrical function-generator card 15 is relied upon to generate
an excitation signal which is supplied to the launch transducer 12,
via power amplifier means 17. The power amplifier is suitably Model
No. 240L, an RF power amplifier product of EIN, Inc., Rochester,
N.Y. This product provides a 50 dB gain, over the range 20 kHz to
10 MHz.
The excitation signal generated by card 15 is a negative pulse
signal, of about 0.3 seconds in duration; after input of this
signal to power amplifier 17, the value of the output signal from
the power amplifier 17 is approximately -300 volts. Card 15 may
suitably be a waveform synthesizer product of Quatech, Inc., Akron,
Ohio, identified by Quatech part No. WSB-100. This waveform
synthesizer provides generation of analog signals independent of
the host computer 14, allowing full processor power to be used for
other tasks, including calculation of waveform data; it has the
capacity to generate an output signal comprising literally
thousands of points in the indicated frequency range. The computer
14, card 15, and power amplifier 17 may be understood to comprise
an ultrasound pulser 44 (shown within the dashed line in FIG. 1);
however its present embodiment as described herein has much more
flexibility than conventional ultrasound pulsers because of the
wide range of electrical excitation signals that may be realized.
(It should nevertheless be understood that a conventional
ultrasound pulser may also be utilized in the present invention, as
shown in FIG. 3.)
A needle syringe 18 is also shown and contains 20 milliliters of a
bone growth factor 27. In the presently preferred embodiment of the
invention, the bone growth factor 27 is TGF-.beta.. This bone
growth factor may suitably be obtained from Genentech, Inc., of
South San Francisco, Calif.
Finally, general signal-processing/display/storage software, for
the signal processing control and operation of the computer is not
shown but will be understood to be a CD-ROM loaded at 19 into the
computer; this software is suitably MATLAB 5, available from The
MathWorks, Inc., Natick, Mass. Further software, also not shown
include the Signal Processing, Optimization and Statistics
Toolboxes, also available from MathWorks, as well as C++ Version 5,
available from the Microsoft Corporation, Bothell, Wash.
In the presently preferred embodiment of this invention and with
additional reference to FIGS. 1 and 2, soft tissue 11 surrounding
bone locale 10 is injected through skin 9, with a bone growth
factor 27 using syringe 18. An ultrasound transducer 12, connected
to an ultrasound pulser 44, is placed next to bone locale 10 with
surrounding soft tissue 11 and skin 9, with sufficient ultrasound
gel to insure efficient acoustic coupling. An ultrasound signal is
transmitted from transducer 12, passes through skin 9, soft tissue
11, and into the bone locale 10. The transmitted ultrasound signal
is generated by pulsing the transducer with a 0.3 microsecond
duration -300 volt square wave. With particular reference to FIG.
2(A), this produces an ultrasound signal with a center frequency of
about 3 MHz, and of about 1 microsecond in duration, thereby
creating a broadband exponentially damped 3 MHz sinusoidal signal,
6. This signal is repeated at a frequency of 4,500 Hz.
In the presently preferred embodiment of the invention, the
ultrasound signal is applied within 10 minutes of the injection of
the bone growth factor, for an initial ultrasound treatment time of
15 minutes. Subsequently, two 15 minute ultrasound treatments per
day are applied, for 7 days total. It should be understood that in
the presently preferred embodiment subsequent ultrasound treatments
are applied without any additional injections of the bone growth
factor. In most cases, ultrasound treatments lasting no more than 1
week to 2 weeks will achieve the indicated objectives regarding
bone healing, bone growth and bone ingrowth; in many cases, only
the single initial ultrasound treatment is required to achieve the
indicated objectives.
The preceding description has proceeded on the basis that a
biophysical stimulus, that is, ultrasound, when used in conjunction
with application of a biochemical compound, that is, a bone growth
factor, can dramatically improve the bone healing properties many
times over that which would be obtained by using either factor
alone. The basis for the above statement is rooted in a fundamental
insight which led the present inventors to their current invention.
This insight is that ultrasound interacts in such a way as to
directly modify the velocities and displacements of the molecules
of the biochemical compound. This modification or "stirring" of the
bone growth factor molecules, which includes an induced drifting of
the molecules towards the surface of the bone, provides a
multiplicative enhancement of the direct effects of the ultrasound
and bone growth factor when each acts individually. This effect is
further enhanced through a small but present local heating
phenomenon and associated increase in local blood flow, induced by
the ultrasound, that affects in a beneficial way the biochemically
treated soft tissue and bone.
It is therefore useful to describe in more detail the basis for the
synergistic behavior arising from application of ultrasound in
conjunction with use of a bone growth factor. A basic principle of
the present invention is that the normal diffusion process of the
molecules of a bone growth factor can be enhanced by the external
ultrasound exposure. This in turn can produce higher concentrations
of the bone growth factor molecules in a shorter time in regions to
be treated. It should be further understood that these higher
concentrations of bone growth factor lead to increases in the
associated binding of the bone growth factors or messengers to
their target cells in the bone, and thus to enhanced activity. She
enhanced activity may also be produced through an induced
microstirring, or displacements induced on the bone growth factor
molecules by the external ultrasound. The basic equations for
describing the above interactions are given by: ##EQU1##
and
In Eqs. 1-2, it should be understood that c=c(x,y,z,t) is the
concentration of the bone growth factor at time, t, and spatial
coordinates (x, y, z) (i.e., the number of bone growth factor
molecules per cubic meter at time, t, and spatial coordinates (x,
y, z)), v.sub.i is the velocity of the i-th molecule, .beta. is the
collision frequency of Langevin, M is the mass of the molecule,
v.sub.a is the velocity of the particles of the medium in which the
bone growth factor molecules are moving, N is random (thermal)
noise force, D is the diffusion coefficient associated with the
molecules, v is the ensemble mean velocity of the molecules, and
.PHI. is the molecule flux density in units of number of molecules
per squared meter second. It should also be understood that
M.beta.(v.sub.a -v.sub.i) is the individual drag force acting on a
single particle, and M.beta.(v.sub.a -v) is the average drag force.
The corresponding contribution to the flux density is equal to
c.multidot.average drag force/(M.beta.).congruent.c (v.sub.a -v).
In the case of a spherical molecule (or messenger) of radius,
R.sub.0, moving in a medium of viscosity, .eta., then M.beta.=6
.pi..eta.R.sub.0. The random force contributes to the diffusion a
term -D.gradient.c, where D=kT/(6 .pi..eta.R.sub.0), where k is
Boltzmann's constant and T is the temperature in degrees
Kelvin.
Another relationship which can be obtained from the definition of
the molecule flux is:
Then, equating Eq. 2 with Eq. 3 leads to the following two
equations: ##EQU2##
It should be understood that, v.sub.a, the acoustic velocity of the
medium particles, can be computed from the linear solution of the
elastic wave equation. Such a solution is widely known in the art,
and a commercial software package even exists for computing it.
This software, Wave2000, may suitably be obtained from CyberLogic,
Inc., located in New York, N.Y.
Two additional equations required to solve for the concentration
c=c(x,y,z,t) of the bone growth factor molecules (or messengers)
are the continuity equations: ##EQU3##
In Eqs. 6 and 7, s is assumed to be the concentration of binding
sites, for the bone growth factor molecules, c.sub.B is assumed to
be the volume concentration of bound messengers, and K.sup.+ and
K.sup.- are the adsorption and desorption rate "coefficients,"
respectively. Solving Eq. 6 for c.sub.B and substituting it in Eq.
7, the following equation can be derived: ##EQU4##
Finally, the divergence of the flux, .gradient..multidot..phi., can
be expressed as ##EQU5##
It should be understood that by substituting Eq. 9 into Eq. 8, a
partial differential equation for the concentration of bone growth
factor molecules, at time, t, and at spatial coordinates, (x,y,z),
is obtained. Solution may be obtained by a number of ways known in
the art. In the presently preferred embodiment, the method of
finite differences is used. A suitable reference for this technique
may be found in the book Numerical Recipes in FORTRAN The Art of
Scientific Programming, Second Edition, by William H. Press, Saul
A. Teukolsky, William T. Vetterling and Brian P. Flannery,
published by Cambridge University Press, Cambridge, England in
1992, and which is incorporated by reference hereinto. The
concentration, c, and flux, .PHI. (as computed according to Eq. 5),
are thus affected by an external ultrasound input, through the
induced motion of the medium particles, as represented by a
non-zero value for v.sub.a. It is to be understood that this
results in synergistic enhancements of bone healing, bone growth
and bone ingrowth effects.
It is useful to provide further analysis of the basis by which are
synergistic behavior with the biophysical and biochemical inputs
may be obtained. To do this, a consideration of the one-dimensional
case is given. The basic equations then reduce to: ##EQU6##
Therefore, in the one-dimensional case, and with the further
simplifying assumptions that K.sup.+ =K.sup.- =s=0, the
concentration, c, of the molecules of the bone growth factor is
obtained by solving Eq. 10. Eq. 11 may then be solved for the
molecule flux, .PHI., in the presence (v.sub.a.noteq.0) and in the
absence (v.sub.a =0) of ultrasound exposure.
It should be further pointed out that the external ultrasound
waveform is responsible for inducing motion of the particles of the
propagation medium (i.e., the soft tissue and bone), as represented
through the velocity, v.sub.a. It is this particle motion that
gives rise to the enhanced effects of the combined stimulations,
through the non-linear interactions with the bone growth factor
molecules. Thus, different ultrasound waveforms will in general
give rise to distinct effects in terms of the bone healing, bone
growth and bone ingrowth. It has been pointed out supra that
algorithms (i.e., computer software) exist for the evaluation of
the induced medium particle velocity. Alternatively, under some
simplifying assumptions, analytic expressions for the medium
velocity, v.sub.a, may also be described. One such example is given
by ##EQU7##
In Eq. 12, v.sub.0 is the induced particle motion of the medium
(i.e., soft tissue) at the surface (i.e., the outer layer of the
skin), .alpha. is the attenuation of the medium, .omega. is the
radian frequency, z is the depth at which the velocity is being
evaluated and z=0 is the outer skin surface, and v.sub.p is the
velocity of the ultrasound wave within the medium. It should be
appreciated that in this characterization any discontinuities in
the medium have been ignored, i.e., a semi-infinite uniform
half-space is assumed.
Yet another example of a particle velocity, v.sub.a, is given by
##EQU8##
In Eq. 13, 1/T is the repetition rate of the signal waveform,
f(.multidot.), and v.sub.g is the group velocity of the ultrasound
wave. In the case of no dispersion, the group velocity, v.sub.g, is
equal to the phase velocity, v.sub.p. In cases of dispersion, the
value of the group velocity, v.sub.g, may most suitably be chosen
to be at the nominal center frequency of the waveform,
f(.multidot.). It should be understood, however, that in the
characterization as described in Eq. 13, the dispersion is assumed
to be negligible. In other cases, it may be most suitable to
compute the full solution to the elastic wave equation, as
disclosed supra, in order to evaluate the particle velocity at any
point in the medium. It should be understood that any functional
description for the ultrasound waveform, f(.multidot.), can be
utilized in the present invention. In the presently preferred
embodiment, f(.multidot.) is an exponentially damped sinusoid of 3
MHz, repeating at 4.5 kHz=1/T. However, any waveform, including but
not limited to continuous sine, pulsed sine, broadband
finite-duration, as well as amplitude and frequency modulated
ultrasound signals can be utilized in realizing the objectives of
the invention.
It should also be pointed out that in the case of a semi-infinite
or infinite medium, the value of v.sub.0 can be computed from the
following expression:
l.sub.a =1/2+L .rho..sub.d v.sub.p v.sub.0.sup.2 (14)
In Eq. 14, .rho..sub.d is the medium (tissue) density, and I.sub.a
is the acoustic (ultrasound) power intensity in Watts per square
meter that enters the tissue at z=0, that is, that enters the skin
surface. An excellent reference for explaining the relationship
between acoustic intensity and medium velocity may be found in the
book entitled Physical Principles of Medical Ultrasonics, by C. R.
Hill, published by Halsted Press, New York, in 1986, and which is
incorporated by reference hereinto.
The preceding has described an analytic basis for the synergistic
effects which are induced by combined application of ultrasound and
biochemical compounds, as discovered by the present inventors. It
should be further appreciated that other mechanisms by which the
ultrasound input can dramatically enhance the activity of the bone
growth factor exist as well. As one such example, the external
ultrasound input can affect directly the binding constants K.sup.+
and K.sup.-, leading to enhanced bone healing results.
Additionally, increased local blood circulation due to application
of ultrasound can significantly improve the bone healing, bone
growth and bone ingrowth effects of a bone growth factor. An
excellent reference for these effects induced on blood flow and
temperature can be found in the book Therapeutic Heat and Cold,
Fourth Edition, edited by Justus F. Lehmann and published by
Williams and Wilkins of Baltimore, Md. in 1990, and incorporated by
reference hereinto. It should be understood that it is the
combination of ultrasound with bone growth factors that produces
the enhanced bone healing, bone growth and bone growth results.
Another embodiment of the invention involves the combined use of
ultrasound with skin surface application of a bone growth factor,
for treating a bone fracture. In this embodiment, the bone growth
factor is not injected through the skin; instead, it is
non-invasively applied to the skin surface overlying the bone to be
treated. The ultrasound transducer is immediately placed onto the
skin where the bone growth factor was applied, and energized by the
ultrasound pulser. Thus it should be understood that a prescribed
amount of a biochemical compound is placed on the skin overlying
the bone to be treated in a living body, and that the ultrasound
transducer, connected to an ultrasound pulser, is acoustically
coupled to the skin and produces an ultrasound signal within the
bone. In this embodiment of the invention, the applied ultrasound,
through the mechanism as described hereinabove, i.e., through the
effects on diffusion of the bone growth factor molecules, serves to
transfer or transport the bone growth factor through the skin and
soft tissue and deliver it to the bone to be treated. In this
alternative embodiment of the invention, and with additional
reference to FIG. 2(B), a specially designed ultrasound signal is
utilized for the first ultrasound treatment, that is the ultrasound
treatment immediately after the bone growth factor is applied to
the skin outer surface. The ultrasound signal consists of a
relatively high intensity 250 mW/cm.sup.2 (SATA) continuous
sinusoid of approximately 1 MHz frequency applied for 5 minutes,
and then followed for an additional 5 minutes at 150 mW/cm.sup.2
(SATA), and ending with 20 additional minutes at 15 mW/cm.sup.2
(SATA). Subsequent ultrasound treatments are carried out using the
15 mW/cm.sup.2 (SATA) continuous sinusoid at 1 MHz frequency for 20
minutes two times per day for 2 weeks total. The selected
ultrasound signal serves to both transport the bone growth factor
through the skin and to synergistically enhance its associated
bioactivity and bioeffectiveness. It should therefore be understood
that, in addition to the transporting of the bone growth factor
through the skin, this embodiment also has associated with it
synergistic enhancements in the healing effects, as described
hereinabove for the embodiment of the invention in which the bone
growth factor was injected through the skin. In this alternative
embodiment, injection by syringe or any other invasive means is
avoided; the bone growth factor is "pushed" or "conveyed" through
the intact skin to the bone. Further, synergistic enhanced response
is also realized by the action of the ultrasound in conjunction
with the bone growth factor, not only through direct effects on
diffusion, but also through associated local increases in blood
flow, temperature increases, as well as effects on the adsorption
and desorption rate coefficients.
It should be appreciated that although ultrasound is one
biophysical stimulus that can synergistically interact with and
enhance the bioeffectiveness of a bone growth factor, other
biophysical stimuli also can be utilized. In one such alternative
embodiment of the invention, acoustic energy, but not ultrasonic,
i.e., mechanical energy having only frequencies below approximately
20,000 cycles per second, is used to stimulate bone growth. In this
alternative embodiment, a vibrating platform is used to generate
dynamic displacements in bone tissue throughout the body. Such a
vibrating platform is well known in the art, and may suitably be
Model No. 4060-15, obtainable from the Bertec Corporation, of
Columbus, Ohio. This model is capable of producing vertical
displacements having a frequency content of up to 1800 Hz. This
biophysical input, that is a mechanical input having sub-ultrasonic
frequency components, has been previously described to have
osteogenic capabilities, that is to promote bone healing, growth
and ingrowth. An example of such a method is given in the two
patents by McLeod et al., U.S. Pat. Nos. 5,103,806 and 5,191,880,
which are incorporated by reference hereinto. In these patents, the
inventors disclose methods for promotion of growth of bone tissue
and the prevention of osteopenia, using mechanical loading of the
bone tissue. In the present alternative embodiment of the
invention, the effects of the biophysical (i.e., mechanical) input
are dramatically enhanced by combining this treatment with a
biochemical one, namely, a therapeutic drug. In this alternative
embodiment, the drug may suitably be Fosamax, available from Merck
& Co., Inc., Whitehouse Station, N.J. It should be understood
that in this embodiment both the biophysical (i.e., mechanical) and
biochemical (i.e., drug) inputs are systemically applied. Thus, the
synergistically enhanced response occurs throughout the skeleton,
and most importantly the therapeutic benefit includes, but is not
limited to, the hips and spine. In the present embodiment of the
invention, the mechanical stimulus is applied for about 10 minutes
twice a week, ideally about 2 hours after ingestion by the patient
of his or her first Fosamax dose that morning; the benefits
obtained under the prescribed regimen are much more dramatic
increases in bone mass and marked reductions in bone loss, as well
as significant reductions in the total number of biophysical (i.e.,
mechanical) treatments required per week and reductions by half in
the required dosage of Fosamax, in contrast to that which is
required without synergistic biochemical and biophysical treatment.
The reduction in drug dosage is particularly beneficial as it
reduces the potential for side-effects.
Although in the alternative embodiment of the invention as
disclosed in the preceding paragraph, mechanical energy (that is,
vibrations inducing displacements and strains) was combined with
biochemical treatment with Fosamax, it should be understood that
any drug which stimulates bone growth, or inhibits bone loss, or
acts on both such aspects of bone physiology and metabolism, may be
utilized. Such drugs can include any biochemical compound, such as
estrogen or estrogen-like compounds, bisphosphonates, calcitonins,
fluorides, anabolic bone agents, anti-resorptive drugs, selective
estrogen receptor modulators, PTH or other therapeutic peptides, or
any bone growth factor. It should be further understood that
although in the present alternative embodiment of the invention, as
described in the preceding paragraph, the biophysical input (i.e.,
mechanical force) and biochemical compound (i.e., drug) are, both
systemically applied, local treatments are also considered to be
within the scope of the present invention. The local nature of the
treatments can be understood to be associated with either the
mechanical stimulus or the biochemical stimulus, or with both. The
synergistic effects due to the externally induced vibratory motion
of the bone and soft tissue in combination with application of the
biochemical compound are responsible for the enhanced bone healing,
bone growth and bone ingrowth results. It should therefore be
additionally understood that a variety of mechanical stimulation
methods may be utilized in alternative embodiments of the present
invention. For example, another method and apparatus for generating
mechanical energy in a living body is described by Bassett et al.,
U.S. Pat. No. 4,928,959 and which is incorporated by reference
hereinto; they disclose method and device for providing active
exercise treatment for a patient suffering from a bone disorder, in
which a patient is subjected to an impact load in order to
stimulate bone growth, with an impact load sensor being used to
monitor the treatment strength. Such methods also benefit greatly
from their synergistic combination with biochemical compounds
according to the invention as disclosed herein.
While the alternative embodiments as described in the preceding two
paragraphs have focussed on the combined use of mechanical energy
at sub-ultrasonic frequencies with biochemical Compounds for
treating bone loss (as in osteoporosis or osteopenia), bone
fracture healing can be treated as well. Thus, in yet a further
alternative embodiment of the invention, bone fracture healing is
therapeutically treated by combining a mechanical stimulus together
with a bone growth factor. In the present embodiment, a bone
fixator enabled with "dynamization" is used to treat a bone
fracture. Dynamization is a method by which a certain amount of
mechanical energy is provided to a bone fracture site, in an effort
to accelerate or otherwise optimize the healing process. An
apparatus for providing such stimuli to a bone fracture is
disclosed in a patent by Faccioli et al., U.S. Pat. No. 5,320,622,
and which is included by reference hereinto. In the present
embodiment, a fibroblast growth factor, FGF-1, is injected into the
fracture site preferably within 5 days of the occurrence of the
fracture, and mechanical stimulation via dynamization is applied
continuously starting 5 additional days after application of the
bone growth factor. The bone growth factor, FGF-1, is suitably
available from Rhone-Poulenc Rorer Pharmaceuticals, Inc., of
Collegeville, Pa. In the present embodiment, bone healing at the
fracture site is significantly enhanced due to the synergistic
interaction of the combined application of mechanical stimulation
and bone growth factor.
It should be further understood that mechanical stimulation at a
fracture site can be achieved not just with "dynamization" as
described in the preceding paragraph, but also with induced
localized vibrations, as for example with a dynamic vibration
shaker, or by induced systemic vibrations, as for example with a
vibrating platform; in either case, the vibrations are to be
understood to be applied in conjunction with use of a bone growth
factor, in order to achieve the objectives of enhanced bone healing
and bone growth. For example, in one yet additional alternative
embodiment of the invention, a vibration shaker generates
relatively high frequency local displacements in a fractured limb.
Such a vibration shaker may suitably be Model No. V-102, available
from Ling Dynamic Systems, Inc., of Yalesville, Conn. This shaker
can generate mechanical vibrations at frequencies of more than 1000
Hertz, and in conjunction with application of a locally applied
bone growth factor, can dramatically enhance the fracture healing
process, over that obtainable with application of either stimuli
individually. In this present alternative embodiment of the
invention, the bone growth factor is FGF-1, suitably available from
Rhone-Poulenc Rorer Pharmaceuticals, Inc., of Collegeville, Pa.
With additional reference to FIG. 4, it should thus be understood
that mechanical (i.e., acoustic, vibrational) stimulation, either
at ultrasonic or below ultrasonic frequencies, whether applied
locally or systemically, when used in conjunction or combination
with a biochemical compound (i.e., a bone growth factor), whether
applied locally or systemically (including topical skin application
or injection), can dramatically and significantly enhance the bone
healing, bone growth and bone ingrowth processes, through a
powerful synergistic interaction, as discovered by the present
inventors. It should additionally be understood that such methods
and apparatuses can find use not only in bone fracture healing (in
fresh, delayed and non-union fractures) and in treatment for
osteoporosis and osteopenia, but also for treatment in the case of
orthopaedic implants, for example to promote bone ingrowth around
an artificial hip or knee. The disclosed invention can also find
use for promoting osteoconduction and osteoinduction around not
only orthopaedic implants, but for incorporation of bone grafts as
well. Such bone grafts include but are not limited to autologous,
bone bank, collagen based, as well as non-bone graft materials. It
should be understood that the bone graft materials may be treated
directly with a bone growth factor, before being placed into a
patient. Subsequently, ultrasound treatment is used to
synergistically enhance the amount of bone ingrowth into and around
the biochemically treated implant. In one such alternative
embodiment of the invention, a non-bone graft material, most
suitably Pro Osteon 500R, available from Interpore Cross
International of Irvine, Calif., is treated first with an
autologous bone growth factor, suitably platelet-derived growth
factor, and surgically implanted into the patient. A low intensity
(20 mW/cm.sup.2 SATA) ultrasound continuous sine signal at 3 MHz is
then applied every other day for thirty minutes for a period of 3
weeks. The effect of the growth factor in combination with the
ultrasound results in dramatically enhanced bone ingrowth,
biomechanical stability and resorption of the non-bone graft
material. A related but alternative embodiment of the invention
utilizes a bone graft substitute known as NOVOS, suitably available
from Stryker Biotech, of Natick, Mass. NOVOS contains type I bone
collagen and Osteogenic Protein-1 (OP-1), and, in this alternative
embodiment, is surgically implanted into a non-union fracture. The
osteogenic proteins are described by Kuberasampath et al., U.S.
Pat. No. 5,840,325, which is incorporated by reference hereinto. A
low intensity (20 mW/cm.sup.2 SATA) ultrasound continuous sine
signal at 3 MHz is then applied every other day for thirty minutes,
starting within 24 hours from the time of the implant, for a period
of 3 weeks. The combination of the ultrasound with OP-1 treated
collagen (i.e., NOVOS) results in dramatically enhanced bone
healing and consolidation at the fracture site.
As yet one further embodiment of the invention, electromagnetic
field ("EMF") energy is used as a biophysical input, in synergistic
conjunction with a bone growth factor. In this alternative
embodiment, mechanical energy is not employed; instead, an
electromagnetic applicator is used to treat a bone which is also
treated with a bone growth factor. The electromagnetic applicator
is most suitably a "pulsed electromagnetic field ("PEMF")
applicator, as available from Orthofix International N.V., located
in Curacao, Netherlands; this applicator is described by Erickson
et al., U.S. Pat. No. 5,195,941, and which is included by reference
hereinto. (In this embodiment, and with additional reference to
FIG. 4, it is to be understood that the ultrasound transducer and
ultrasound pulser shown in FIG. 1 are replaced by the PEMF
stimulator.) In this alternative embodiment, TGF-.beta. is injected
with a syringe into the soft tissue overlying a non-union bone
fracture. The PEMF applicator is applied to the fractured limb on
the same day, within 1 hour of the injection of the bone growth
factor, for a total treatment time of 1.5 hours. Subsequently, the
PEMF is applied daily for 1.5 hours for approximately 2 weeks, in
order that healing of the non-union may be stimulated sufficiently
to go on to heal fully, through the synergistic interaction of the
external electromagnetic field.(i.e., the PEMF) with the bone
growth factor (i.e., the TGF-.beta.). It should be understood that
the synergistit-bone healing response is achieved, in the case of
electromagnetic stimulation, largely through direct effects on the
K.sup.+ and K.sup.- adsorption, and desorption rate coefficients,
respectively; however, effects on diffusion and blood flow also are
mechanisms through which enhanced effects on bone healing, bone
growth and bone ingrowth occur. It should be further appreciated
that any type of electromagnetic field applicator or signal may be
utilized in conjunction with application of a bone growth factor,
each either locally or systemically applied. The electromagnetic
field energy may further be understood to be applied either
inductively, capacitively or through electrodes in contact with the
living body.
It should be appreciated that the various biophysical modalities,
that is, ultrasonic, mechanical (at sub-ultrasonic frequencies) and
electromagnetic energies, can be utilized with a variety of signal
waveforms (i.e., temporal characteristics), including continuous
sinusoid, pulsed sinusoid, broadband repetitive pulses, and
amplitude-modulated and frequency-modulated waveforms. It is,
however, to be understood that such application of biophysical
signals with specific temporal characteristics is to be utilized in
conjunction with a biochemical compound or bone growth factor in
order that the indicated objectives can be achieved. It should also
be appreciated that the biochemical compound may often be contained
in a. convenient matrix which is biocompatible and which is used as
a "vehicle" to carry the "active" bone growth factor or component.
As one such example, TGF-.beta.may be mixed with a basic ultrasound
couplant or gel, and the mixture applied to the skin. The gel or,
matrix serves a dual purpose in this case: (i) as a convenient
means to maintain the growth factor in a confined region; and (ii)
to efficiently couple the ultrasound signal from an ultrasound
transducer to the skin.
While the previously disclosed embodiments of the invention have
focused on enhancing bone healing, bone growth and bone ingrowth,
it should nevertheless, be understood that the methods disclosed
herein can find therapeutic application not only to bone but to
other musculoskeletal tissues as well. For example, in an
alternative embodiment of the invention, osteoarthritis at the knee
is treated through the combined application of ultrasound with a
biochemical compound. In the present alternative embodiment, and
with additional reference to FIG. 1, a 3.5 MHz continuous
sinusoidal signal having a spatial-average temporal-average power
intensity of 15 mW/cm.sup.2 is applied to the skin overlying the
knee to be treated. In FIG. 1, the cartilage is not shown but
understood to be adjacent to bone 10. In the present embodiment,
the biochemical compound is most suitably Synvisc comprising sodium
hyaluronate. Synvisc is available from Biomatrix, Inc., of
Ridgefield, N. J. It should be understood that Synvisc is injected
into the cartilage of the knee to be treated using syringe 18. The
knee is then treated with ultrasound, which together with the
biochemical treatment (that is, the Synvisc) leads to significantly
enhanced reductions in pain and improved function, as compared with
that obtained using either (i.e., the ultrasound or biochemical)
treatment alone. In the presently preferred alternative embodiment,
only one ultrasound treatment (that is, one treatment in
conjunction with only one injection of Synvisc) is used, with
dramatic improvements in pain relief and function achieved.
It should therefore be understood that all of the previous
variations of the invention as disclosed hereinabove for
applications to bone apply as well to musculoskeletal tissue in
general. Therefore, and with additional reference to FIG. 5,
application of a biophysical stimulus or input in conjunction with
application of a prescribed amount of a biochemical compound to a
living body can be understood to lead to synergistically enhanced
musculoskeletal tissue healing, growth and repair. Further, it
should be appreciated that the musculoskeletal tissue can include
not only bone, but ligament, tendon and cartilage, as well.
Moreover, the biophysical stimulus can be applied locally or
systemically, and be of either electromagnetic field energy or
mechanical energy at sub-ultrasonic frequencies (i.e., vibrational)
or at ultrasonic frequencies. The biochemical compound can itself
be applied locally or systemically as well (e.g., be injected
through or topically applied to the skin), and can be understood to
be comprised of any substance or class of substances that can
interact biochemically with the musculoskeletal tissue to be
treated. This interaction is enhanced synergistically through
application of the biophysical Stimulus, through effects on
diffusion, blood flow, temperature and adsorption and desorption
rate coefficients, as described hereinabove. It should also be
generally appreciated that the amount of biochemical compound
prescribed will be a function of the type of compound and the
particular therapeutic application; however, amounts utilized are
generally much less when biophysical inputs are employed according
to the methods as disclosed herein, in comparison to that required
when biochemical compounds alone are utilized.
With additional reference to FIG. 5, and in particular to the
portion shown by the dashed arrows, it should be understood that
the application of a biochemical compound to the musculoskeletal
tissue, i.e., to bone, ligament, cartilage or tendon, can also be
achieved non-invasively by concurrent application of ultrasound. In
such an alternative embodiment, a prescribed amount of a
biochemical compound is applied to the skin; that is, a prescribed
amount of the biochemical compound is placed on the skin overlying
the musculoskeletal tissue to be treated. An ultrasound transducer
is then acoustically coupled to the skin overlying the
musculoskeletal tissue to be treated, and connected to an
ultrasound pulser, so that an ultrasound signal is produced within
the musculoskeletal tissue. The action of the ultrasound causes the
biochemical compound to be transported to the musculoskeletal
tissue being treated, without the need for invasive needle
injection. Additionally, the ultrasound interacts in a synergistic
fashion with the biochemical compound to obtain enhanced
therapeutic effects on the musculoskeletal tissue.
Finally, it is important to emphasize that the disclosed invention
and its various embodiments rely on the concurrent use of a
biophysical stimulus with a biochemical one. This concurrent or
conjunctive use is a crucial aspect of the present invention, as it
is the basis by which the indicated objectives of synergistically
enhanced musculoskeletal tissue healing and growth are achieved. It
should be further appreciated that such concurrent or conjunctive
use of the biophysical and biochemical stimuli in the context of
the current invention may be carried out in a number of ways. For
example, the biophysical stimuli can be applied almost immediately
(e.g., within several minutes) after the biochemical compound is
injected, ingested or otherwise utilized. Alternatively, the
biophysical stimuli can be applied after a more significant period
of time has elapsed after utilization or application of the
biochemical compound. However, the best results are obtained when
the biophysical stimulus is applied within twenty-four (24) hours
after application of the biochemical treatment. However, good
results are also obtained when the biophysical stimulus is applied
as many as three (3) months after application of the biochemical
treatment. Thus the present invention should be understood to
include both long and short time periods between application of the
biochemical compound and subsequent application or applications of
the biophysical stimuli, so that the meaning of the terms
"concurrent," "conjunctive," "combined with" or "in combination
with" should be understood in this relatively broad sense. It
should lastly be additionally understood that "pre-biochemical
treatment" with a biophysical stimuli, that is, application of the
biophysical stimulus before utilization of a biochemical stimuli,
which serves to "condition" the musculoskeletal tissue, in addition
to "post-biochemical treatment" with a biophysical stimuli, can
lead to enhanced musculoskeletal tissue healing and growth as
well.
While several embodiments of the present invention have been
disclosed hereinabove, it is to be understood that these
embodiments are given by example only and not in a limiting sense.
Those skilled in the art may make various modifications and
additions to the preferred embodiments chosen to illustrate the
invention without departing from the spirit and scope of the
present contribution to the art. Accordingly, it is to be realized
that the patent protection sought and to be afforded hereby shall
be deemed to extend to the subject matter claimed and all
equivalence thereof fairly within the scope of the invention.
It will be seen that the described invention meets all stated
objectives as to therapeutic treatment in vivo of bone tissue
specifically and musculoskeletal tissue in general, with specific
advantages that include but are not limited to the following:
(1) Significantly enhanced healing effects due to the concurrent
use of a biophysical stimulus with a biochemical stimulus;
(2) Capability to avoid invasive (e.g., needle injection) for
delivery of bone growth and other biochemical factors to the
treated musculoskeletal tissue;
(3) Achievement of a dramatic reduction in the required treatment,
including both in terms of number of minutes per treatment and even
more importantly also the number of total treatments required;
(4) Synergistic response due to the conjunctive use of a
biophysical and biochemical stimuli, leading to much more enhanced
effects over that which would be obtained using only one of the
stimuli;
(5) Description of specific biophysical stimuli, including
ultrasonic, mechanical and electromagnetic, that may be used to
achieve dramatically enhanced healing and growth, when used in
conjunction with a biochemical compound;
(6) Description of a mathematical-model to characterize the
synergistic interaction of ultrasonic and biochemical stimuli,
which may be used in the design of signals with maximal healing
effects;
(7) The convenience and practicality of a much more effective
method for therapeutically treating bone and other musculoskeletal
tissue, allowing in many cases even one single combined
application/treatment to achieve the indicated objectives;
(8) Reduction in the potential for side-effects from drugs, because
of the smaller doses typically required;
(9) Greater acceptance by the medical and patient communities, and
also by third-party-payers, because of its enhanced effectiveness;
and
(10) The nature of the apparatus as described here serves best the
purposes of further exploration for obtaining maximally effective
signals and dosage regimens that can be correlated for the
indicated objectives. The embodiments of the invention as described
above can explore a wide range of experimental configurations.
Their use is expected to lead to the development of compact and
efficient apparatus for obtaining the indicated objectives. For
example, a compact electronic analog implementation can easily be
constructed if economy and simplicity are the primary objectives.
Other systems which rely on combined analog and digital electronics
are more expensive, yet can be more flexible in terms of the range
of applications which can be addressed (e.g., systems for a single
therapeutic application to bone fracture healing, versus systems
for therapeutic applications to a variety of musculoskeletal
tissues and disorders). Further, systems can either be built as a
stand-alone unit or as part of a PC-based system.
* * * * *